Publications by authors named "Bezieau S"
encodes a human long noncoding RNA (lncRNA) adjacent to , a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here, we report our findings in three unrelated children with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination - a phenotype that is distinct from the phenotypes of patients with haploinsufficiency.
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- Colorectal cancer (CRC) is a major health concern, and understanding how genetic and environmental factors interact can help identify at-risk groups.
- This study analyzed data from over 45,000 CRC cases to assess both multiplicative and additive interactions between genetic risk scores and various environmental factors, finding no multiplicative interactions but significant additive ones for high genetic susceptibility individuals.
- Results suggest that individuals with high genetic risk could benefit more from lifestyle interventions like reducing alcohol intake or increasing fruit and fiber consumption, emphasizing the need for targeted prevention strategies in CRC care.
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- - This study examines the link between rare variants in the cullin-3 ubiquitin ligase (CUL3) gene and neurodevelopmental disorders (NDDs), gathering data from multiple centers to explore genetic mutations and their clinical impacts.
- - Researchers identified 37 individuals with CUL3 variants, most of which result in loss-of-function (LoF), leading to intellectual disabilities and possibly autistic traits; specific mechanisms affecting protein stability were also investigated.
- - The findings enhance the understanding of NDDs associated with CUL3 mutations, suggesting that LoF variants are the main cause, which could help inform future diagnostics and treatment strategies.
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- Researchers studied mutations in a gene that affects a key protein involved in cell signaling, which is linked to severe health issues like impaired immunity in patients.
- The mutations were found to disrupt normal cell behavior by promoting excessive cell growth and responses to immune signals, specifically T cell receptor stimulation.
- The mutant protein was shown to interfere with a regulatory protein, leading to heightened activity of important signaling pathways that contribute to cell growth and survival.
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- Glutathione synthetase deficiency is a rare genetic disorder caused by mutations in the GSS gene, leading to varying severity levels, from mild hemolytic anemia to severe neurological issues and even neonatal death.
- A study on two fetal siblings revealed multiple congenital anomalies, such as limb malformations, cleft palate, and heart defects, linked to specific genetic variants in the GSS gene.
- Genome sequencing and analysis indicated that these genetic variants likely caused disruptions in protein expression and metabolic processes, suggesting a broader range of phenotypic effects associated with glutathione synthetase deficiency.
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- * Many forms of intellectual disability prevalent globally are monogenic diseases, with a notable portion linked to genes in the ubiquitin-proteasome system, which regulates protein maintenance.
- * A new category of neurodevelopmental disorders, termed "neurodevelopmental proteasomopathies," is emerging, characterized by cognitive impairments and various clinical features, though the underlying molecular mechanisms are still not well understood.
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- * These disorders result in developmental issues, particularly affecting neural development and causing physical abnormalities like craniofacial defects and heart malformations.
- * The paper suggests that neural crest cells, which play a crucial role in forming craniofacial structures and heart components, may be particularly affected by disruptions in protein homeostasis, urging further research for potential treatments.
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- Dysmorphologists face challenges due to the diverse phenotypic variability of human faces, particularly when using Next-Generation Phenotyping (NGP) tools, which are often trained on limited data.
- To address this, the GestaltMatcher Database (GMDB) was created, compiling over 10,980 facial images from various global populations, significantly improving the representation of underrepresented ancestries, especially African and Asian patients.
- The study found that incorporating data from non-European patients enhanced NGP accuracy by over 11% without compromising performance for European patients, highlighting the importance of diverse datasets in identifying genetic disorders.
Primary proteasomopathies have recently emerged as a new class of rare early-onset neurodevelopmental disorders (NDDs) caused by pathogenic variants in the PSMB1, PSMC1, PSMC3, or PSMD12 proteasome genes. Proteasomes are large multi-subunit protein complexes that maintain cellular protein homeostasis by clearing ubiquitin-tagged damaged, misfolded, or unnecessary proteins. In this study, we have identified PSMD11 as an additional proteasome gene in which pathogenic variation is associated with an NDD-causing proteasomopathy.
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- Consumption of fiber, fruits, and vegetables may lower the risk of colorectal cancer (CRC), but genetic factors might influence this connection.
- A large study involving nearly 70,000 participants identified two significant genetic variants linked to dietary intake and CRC risk using advanced statistical methods.
- The findings suggest specific genetic loci (SLC26A3 and NEGR1) may affect how fiber and fruit consumption interacts with CRC risk, highlighting the need for more research on the underlying mechanisms.
Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV.
View Article and Find Full Text PDFIt remains unknown whether adiposity subtypes are differentially associated with colorectal cancer (CRC). To move beyond single-trait anthropometric indicators, we derived four multi-trait body shape phenotypes reflecting adiposity subtypes from principal components analysis on body mass index, height, weight, waist-to-hip ratio, and waist and hip circumference. A generally obese (PC1) and a tall, centrally obese (PC3) body shape were both positively associated with CRC risk in observational analyses in 329,828 UK Biobank participants (3728 cases).
View Article and Find Full Text PDFPurpose: Imbalances in protein homeostasis affect human brain development, with the ubiquitin-proteasome system (UPS) and autophagy playing crucial roles in neurodevelopmental disorders (NDD). This study explores the impact of biallelic USP14 variants on neurodevelopment, focusing on its role as a key hub connecting UPS and autophagy.
Methods: Here, we identified biallelic USP14 variants in 4 individuals from 3 unrelated families: 1 fetus, a newborn with a syndromic NDD and 2 siblings affected by a progressive neurological disease.
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- The study investigates the concept of incomplete penetrance in neurodevelopmental disorders, where some individuals carry pathogenic genetic variants but remain asymptomatic.
- Between 2020 and 2022, researchers collaborated with a French network to analyze families where affected individuals had inherited these variants from symptom-free parents, finding 12 cases with significant genetic findings.
- The results suggest that incomplete penetrance may be more common than previously acknowledged, highlighting its importance for genetic interpretation, counseling, and future research into its underlying mechanisms.
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- The ubiquitin-proteasome system (UPS) is a crucial pathway in eukaryotic cells that helps maintain protein balance, regulates cell functions, and dictates cell survival and death.
- Proteins marked for degradation through the UPS are tagged with ubiquitin chains and broken down by 26S proteasomes.
- Recent findings link certain proteasome dysfunctions to rare neurodevelopmental disorders, known as "neurodevelopmental proteasomopathies," which can lead to delays in development, behavioral issues, and various physical anomalies, prompting research into potential biomarkers for diagnosis and treatment.
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- * Researchers found 23 specific changes in a gene related to this complex that affect 38 people, leading to problems with brain cell growth and learning in animals.
- * By targeting certain stress response proteins, they discovered ways to help fix some of the immune issues caused by these disorders, leading to new ideas for treatments.
The calcium/calmodulin-dependent protein kinase type 2 (CAMK2) family consists of four different isozymes, encoded by four different genes-CAMK2A, CAMK2B, CAMK2G, and CAMK2D-of which the first three have been associated recently with neurodevelopmental disorders. CAMK2D is one of the major CAMK2 proteins expressed in the heart and has been associated with cardiac anomalies. Although this CAMK2 isoform is also known to be one of the major CAMK2 subtypes expressed during early brain development, it has never been linked with neurodevelopmental disorders until now.
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- Researchers identified a genetic cause for a rare neurodevelopmental syndrome characterized by cognitive impairment, distinctive facial features, and various additional health issues.
- They studied six individuals from unrelated families using exome sequencing and created models with human stem cells and zebrafish to examine the effects of the identified gene, CACHD1.
- Results showed that mutations in CACHD1 lead to significant neural development problems and physical defects, linking it directly to the syndrome’s symptoms.
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- High consumption of red and processed meats is linked to an increased risk of colorectal cancer, with a study analyzing data from over 29,000 cancer cases and 39,000 control subjects confirming this association.
- The research identified two significant genetic markers (SNPs) that interact with meat consumption levels, suggesting that certain genetic variants can influence individual cancer risk based on dietary habits.
- These findings highlight the potential for using genetic information to better understand colorectal cancer risks related to diet, which may lead to personalized dietary recommendations for specific population subgroups.
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- DYRK1A Syndrome is caused by mutations in the DYRK1A gene, leading to global developmental delays, intellectual disability, and common physical issues like low birth weight and microcephaly.
- The study compiled growth data from 92 individuals with the syndrome, utilizing various sources including pediatric records and scientific literature.
- New growth charts were created for key measurements (height, weight, BMI, occipitofrontal circumference) for children aged 0-5 years, providing a useful tool for managing patients with DYRK1A Syndrome.
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- BRCA1 and BRCA2 genes are essential for repairing DNA damage, and their mutations can predict how sensitive high-grade ovarian cancer (HGOC) is to certain treatments, but current testing methods are expensive and slow.
- This study introduces a deep learning classifier that predicts BRCA mutations using whole slide images of HGOC, developed from a substantial patient cohort, and shows promise in increasing efficiency and accuracy in testing.
- The classifier achieved high performance metrics, suggesting that it can effectively detect phenotypic changes linked to BRCA mutations, making it a potential prescreening tool for future use.
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- Observational studies have hinted that certain white blood cells, especially eosinophils and neutrophils, might play roles in the risk of developing colorectal cancer (CRC), but more direct causal connections needed to be established.
- This research analyzed data from almost 600,000 individuals to explore the impact of various white blood cell types (like basophils, eosinophils, and lymphocytes) on CRC risk, using a technique called Mendelian randomization.
- Results indicated that higher counts of eosinophils and lymphocytes could offer protective effects against CRC, reinforcing the importance of investigating how these immune cells relate to cancer development further.
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- The significant phenotypic variability of human faces complicates the work of dysmorphologists by challenging Next-Generation Phenotyping (NGP) tools, especially when analyzing patients from diverse genetic backgrounds.
- The research established the GestaltMatcher Database (GMDB), which includes over 10,000 facial images from patients with rare genetic disorders worldwide, striving to improve representation of underrepresented populations, particularly Asian and African patients.
- The analysis showed that incorporating data from non-European patients enhanced the accuracy of NGP in diagnosing facial disorders without negatively affecting performance on European patients, emphasizing the need for more diverse datasets in medical genetics.
Background: Molecular diagnosis of neurodevelopmental disorders (NDDs) is mainly based on exome sequencing (ES), with a diagnostic yield of 31% for isolated and 53% for syndromic NDD. As sequencing costs decrease, genome sequencing (GS) is gradually replacing ES for genome-wide molecular testing. As many variants detected by GS only are in deep intronic or non-coding regions, the interpretation of their impact may be difficult.
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